Immunology Lecture: Organ Transplantation

Immunology Lecture #12: Organ Transplantation

Part A: T Cell Development, Activation, and MHC Restriction

  • T Cell Development & MHC Restriction

    • Positive Selection

T Cell Activation and MHC Restriction

  • B cells: B cell receptors (BCR) bind to free antigens.

  • T cells: T cell receptors (TCR) bind MHC + antigen.

    • CD4 T cells: TCR binds to MHC-II + antigen.

    • CD8 T cells: TCR binds to MHC-I + antigen.

Human MHC Class I and II Isotypes Functionality

  • MHC Class I Isotypes:

    • 6 HLA class I isotypes.

    • Beta2M: Monomorphic.

  • MHC Class II Isotypes:

    • 5 HLA class II isotypes.

    • Oligomorphic: Presenting few changes.

    • Monomorphic: Existing in only one form.

    • Polymorphic: Existing in many forms with many gene variants.

Definitions

  • Polymorphic: Existing in multiple variants.

  • Genotype: The collection of genes in an individual, referring to a small segment of a chromosome.

  • Allotype: Differences in MHC genes encoding variations of proteins.

  • Highly Polymorphic Genes: Result in a large number of allotypes.

Major Histocompatibility Complex (MHC)

  • HLA: Human version of MHC, a group of genes on chromosome 6.

    • Over 200 genes categorized into:

    • Class I: Three main genes - HLA-A, HLA-B, HLA-C, found on almost all cells.

      • Display peptides to the immune system for self-destruction of infected cells.

    • Class II: Six main genes - HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1, predominantly on immune cells.

  • Peptides: Exported fragments displayed by MHC proteins; recognized as foreign if originating from pathogens leading to immune response.

Allelic Associations and Diseases

  • Over 100 diseases linked to different HLA alleles.

    • Example: HLA-B27 associated with ankylosing spondylitis.

Part B: Organ Transplantation: Problems

Introduction to Organ Transplantation Terminology

  • Autograft: Autologous tissue transplantation.

  • Isograft: Isogeneic (synonymous with syngeneic) - tissue from genetically identical individuals (e.g., identical twins).

  • Allograft: Allogeneic - genetically non-identical tissue from the same species.

  • Xenograft: Xenogeneic - recipient from a different species (e.g., pig heart valve).

Frequency and Statistics of Solid Organ Transplantation (2012)

  • Number of organs transplanted per million population:

    • 0-2.4

    • 2.5-9.9

    • 10-24.9

    • 25-49.9

    • 50-74.9

    • ≥75

Organ Transplant Statistics (2014, USA)

Tissue

No. of Grafts Transplanted

5-Year Graft Survival

Kidney

17,815

81.4%

Liver

6,729

68.3%

Heart

2,679

74.0%

Pancreas

954

53.4%

Lung

1,949

50.6%

Intestine

139

~48.4%

Cornea

~45,000

~70%

HSC (Hematopoietic Stem Cells)

~20,000

>80%

Host vs Graft Disease (Tissue Rejection)

  • Definition: When recipient's immune system attacks transplanted tissue as foreign.

  • Mechanism: Recognition of transplant’s donor HLA by the host immune system.

  • Transplant Rejection Types:

    • Hyperacute: Immediate reaction during surgery due to preformed antibodies (e.g., ABO blood incompatibility).

    • Acute: Develops weeks to months post-transplant, T-cell mediated.

    • Chronic: Months to years after the transplant, leading to graft atrophy.

T-cell Recognition of Antigens is MHC-restricted

  • Specificity defined by both peptide and MHC molecule.

    • If TCR recognizes foreign peptide on self-MHC, activation occurs leading to proliferation and differentiation.

Immunosuppressant Strategies

  • Pharmacological Immunotherapy

    • Corticosteroid Therapy: Reduces inflammation. Targets various cytokines including IL-1, TNF-α, and GM-CSF.

    • Calcineurin Inhibitors: Cyclosporin A & tacrolimus inhibit T-cell activation by blocking IL-2 production.

    • Other agents: Azathioprine, mycophenolic acid.

Mechanisms of Graft Rejection

  • Direct Pathway: Donor dendritic cells activate recipient’s T lymphocytes.

  • Indirect Pathway: Recipient dendritic cells present donor HLA to T lymphocytes.

Graft vs Host Disease (GVHD)

  • Occurs when donor’s T cells attack the recipient’s tissues, especially in bone marrow transplants.

    • Symptoms include skin rashes, gastrointestinal distress.

    • Treatment involves corticosteroids and immunosuppressants to mitigate T-cell response.

Case Study: John Wells

  • Initially diagnosed with aplastic anemia; underwent bone marrow transplant from HLA-identical brother.

  • Developed acute GVHD 24 days post-transplant with manifests such as skin rash and diarrhea.

    • Treatment: Corticosteroids administered but gastrointestinal symptoms remained severe.

Recent Trends in Transplantation

  • Xenotransplantation Research: Focuses on genetic modifications in pigs to lessen rejection risk. Deletion of genes like GGTA1 and addition of human genes like DAF have been explored.

Conclusion

  • The need for organ transplants continues to exceed supply, emphasizing the importance in both organ donation and advances in xenotransplantation possibilities.

Additional Notes

  • To join the organ donor registry or bone marrow registry, visit donation websites.

Sources: The Immune System, 4th ed. (Garland Science 2015), Janeway's Immunobiology, 9th ed. (Garland Science 2017)